Concurrent modulation of 5-fluorouracil with methotrexate and L-leucovorin: An effective and moderately toxic regimen for the treatment of advanced colorectal carcinoma - A multicenter phase II study of the Southern Italy Cooperative Oncology Group

Aims and background: Methotrexate (MTX) and leucovorin (LV) can enhance the cytotoxicity of 8-fluorouracil (5FU) by modifying its metabolic pathway in side target cells. Some preclinical studies and clinical trials have sugges ted that the concurrent or sequential double modulation of 5FU by means of MTX and LV may give a higher activity than single biochemical modulations. The purpose of our phase II study was to assess the activity and toxicity o f a biweekly regimen including MTX, levo-LV and 5FU in colorectal cancer pa tients. Methods: From July 1994 to May 1997, 100 consecutive patients affected by a dvanced or metastatic colorectal carcinoma were given MTX, 750 mg/m(2) iv ( 2-h infusion) on day 1, and levo-LV, 250 mg/m(2) iv (2-h infusion) followed by 5FU, 800 mg/m(2) iv bolus on day 2, every two weeks. Patients were trea ted until complete response or progressive disease was documented, or for a maximum of 16 courses. Results: Among 97 eligible patients, 5 complete and 25 partial responses we re obtained, giving an overall response rate of 31% (95% exact confidence l imits, 22-41%), Response rate was significantly higher in patients with a g ood (ECOG scale 0) than with a poor (ECOG scale 1 or 2) performance status (40% versus 17%, P <0.02). Median time to treatment failure was 27 weeks, m edian survival time was 63 (95% confidence limits, 54-71) weeks, and 2- and 3-year probability of survival were 34% and 12%, respectively. Performance status was the only pretreatment characteristic significantly affecting th e outcome of patients. Indeed, median survival time was 94 weeks for patien ts with a performance status = 0 and 37 weeks for patients with a performan ce status greater than or equal to 1 (P <0.05). Toxicity of the treatment w as low and manageable; grade 3 to 4 leukopenia affected 8% of patients, whe reas grade 3 diarrhea and mucositis occurred in 5% and 4%, respectively. Conclusions: The double biochemical modulation of 5FU by MTX and levo-LV is at least as effective as, and probably more effective than, the single mod ulation by MTX or by LV, It may therefore represent a therapeutic option fo r the palliative treatment of patients with advanced colorectal carcinoma.